Outpatient Treatment of Confirmed COVID-19
Authors: David J. Sullivan, Massimo Franchini, Jonathon W. Senefeld, Michael J. Joyner, Arturo Casadevall, Daniele Focosi
Journal: Annals of Internal Medicine (2023)

LettersMay 2023Outpatient Treatment of Confirmed COVID-19FREEDavid J. Sullivan, MD, Massimo Franchini, MD, Jonathon W. Senefeld, PhD, Michael J. Joyner, MD, Arturo Casadevall, MD, PhD, Daniele Focosi, MDDavid J. Sullivan, MDJohns Hopkins University, Baltimore, MarylandSearch for more papers by this author, Massimo Franchini, MDMantua Hospital, Mantova, ItalySearch for more papers by this author, Jonathon W. Senefeld, PhDMayo Clinic, Rochester, MinnesotaSearch for more papers by this author, Michael J. Joyner, MDMayo Clinic, Rochester, MinnesotaSearch for more papers by this author, Arturo Casadevall, MD, PhDJohns Hopkins University, Baltimore, MarylandSearch for more papers by this author, Daniele Focosi, MDPisa University Hospital, Pisa, ItalySearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L23-0099 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR: We read with dismay Sommer and colleagues' living, rapid review (1) and the American College of Physicians' living, rapid practice points (2) on outpatient treatment of COVID-19. We fully understand how difficult it can be to update living guidelines during a pandemic but also recognize their relevant implications for public health. Here, we refute several recommendations made by the authors.Practice point 1 recommends “molnupiravir to treat patients with confirmed mild to moderate COVID-19 in the outpatient setting who are within 5 to 7 days of the onset of symptoms and at high risk for progressing to severe disease” (2). However, on 17 October 2022, the PANORAMIC (Molnupiravir Plus Usual Care Versus Usual Care Alone as Early Treatment for Adults With COVID-19 at Increased Risk of Adverse Outcomes) randomized controlled trial (RCT) involving 25 783 outpatients (98% fully vaccinated) who initiated treatment with molnupiravir at a median of 3 days since onset of symptoms reported no evidence for reduction in hospitalization or mortality (3). This follows the 30% efficacy of the MOVe-OUT (Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients) RCT sponsored by Merck Sharp and Dohme (4).Practice points 9 to 11 recommend different anti–spike monoclonal antibodies when “considered effective against a SARS-CoV-2 variant or subvariant locally in circulation” (2). Viral sequencing flash surveys typically report cocktails of lineage, but the turnaround time is incompatible with early administration. With such recommendations, we are concerned that even minor representations of sensitive lineages in flash surveys could continue to justify inappropriate prescription of ineffective monoclonal antibodies (5).Practice point 12 recommends against “convalescent plasma to treat patients with confirmed mild to moderate COVID-19 in the outpatient setting” (2). This recommendation surprised us, because this is exactly the setting where convalescent plasma has been proved effective at preventing hospitalizations in both immunocompetent (6) and immunocompromised (7) patients. Moreover, Sommer and colleagues declared this outcome in the protocol registered on PROSPERO but did not report it in their published review (1).Five published RCTs evaluated convalescent plasma as a therapy for outpatients (8). Sommer and colleagues combined the most efficacious RCT with the least efficacious RCT to report a risk ratio of 0.70 (95% CI, 0.30 to 1.65). Combination of all 5 RCTs produces an odds ratio of 0.64 (CI, 0.45 to 0.92), which changes to 0.51 (CI, 0.28 to 0.91) when given early and high-titer plasma therapy (8). Furthermore, the 2 RCTs contrasted should not have been compared, because1 trial used 1 methylene blue–treated plasma, which represents a different product. Convalescent plasma halves mortality in immunocompromised patients (7), preserves efficacy against current variants (9), and likely represents the only antiviral that is affordable to low- and-middle income countries. It is currently authorized for emergency use by the U.S. Food and Drug Administration and recommended by the Association for the Advancement of Blood & Biotherapies, National Comprehensive Cancer Network, and Ninth European Conference on Infections in Leukaemia guidelines.On the basis of these concerns, we urge a timely review of these guidelines.References1. Sommer I, Dobrescu A, Ledinger D, et al. Outpatient treatment of confirmed COVID-19: a living, rapid review for the American College of Physicians. Ann Intern Med. 2023;176:92-104. [PMID: 36442056] doi:10.7326/M22-2202 LinkGoogle Scholar2. Qaseem A, Yost J, Miller MC, et al; Scientific Medical Policy Committee of the American College of Physicians. Outpatient treatment of confirmed COVID-19: living, rapid practice points from the American College of Physicians (version 1). Ann Intern Med. 2023;176:115-124. [PMID: 36442061] doi:10.7326/M22-2249 LinkGoogle Scholar3. Butler CC, Hobbs FDR, Gbinigie OA, et al; PANORAMIC Trial Collaborative Group. Molnupiravir Plus Usual Care Versus Usual Care Alone as Early Treatment for Adults With COVID-19 at Increased Risk of Adverse Outcomes (PANORAMIC): an open-label, platform-adaptive randomised controlled trial. Lancet. 2023;401:281-293. [PMID: 36566761] doi:10.1016/S0140-6736(22)02597-1 CrossrefMedlineGoogle Scholar4. Jayk Bernal A, Gomes da Silva MM, Musungaie DB, et al; MOVe-OUT Study Group. Molnupiravir for Oral treatment of Covid-19 in nonhospitalized patients. N Engl J Med. 2022;386:509-520. [PMID: 34914868] doi:10.1056/NEJMoa2116044 CrossrefMedlineGoogle Scholar5. Anderson TS, O’Donoghue A, Mechanic O, et al. Administration of anti-SARS-CoV-2 monoclonal antibodies after US Food and Drug Administration deauthorization. JAMA Netw Open. 2022;5:e2228997. [PMID: 36036937] doi:10.1001/jamanetworkopen.2022.28997 CrossrefMedlineGoogle Scholar6. Sullivan DJ, Gebo KA, Shoham S, et al. Early outpatient treatment for COVID-19 with convalescent plasma. N Engl J Med. 2022;386:1700-1711. [PMID: 35353960] doi:10.1056/NEJMoa2119657 CrossrefMedlineGoogle Scholar7. Senefeld JW, Franchini M, Mengoli C, et al. COVID-19 convalescent plasma for the treatment of immunocompromised patients: a systematic review and meta-analysis. JAMA Netw Open. 2023;6:e2250647. [PMID: 36633846] doi:10.1001/jamanetworkopen.2022.50647 CrossrefMedlineGoogle Scholar8. Levine AC, Fukuta Y, Huaman MA, et al. COVID-19 convalescent plasma outpatient therapy to prevent outpatient hospitalization: a meta-analysis of individual participant data from five randomized trials. Clin Infect Dis. 2023. [PMID: 36809473] doi:10.1093/cid/ciad088 CrossrefMedlineGoogle Scholar9. Sullivan DJ, Franchini M, Senefeld JW, et al. Plasma after both SARS-CoV-2 boosted vaccination and COVID-19 potently neutralizes BQ.1.1 and XBB.1 [Preprint]. bio. Rxiv. 2022. [PMID: 36482971] MedlineGoogle Scholar Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAuthors: David J. Sullivan, MD; Massimo Franchini, MD; Jonathon W. Senefeld, PhD; Michael J. Joyner, MD; Arturo Casadevall, MD, PhD; Daniele Focosi, MDAffiliations: Johns Hopkins University, Baltimore, MarylandMantua Hospital, Mantova, ItalyMayo Clinic, Rochester, MinnesotaPisa University Hospital, Pisa, ItalyDisclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L23-0099.This article was published at Annals.org on 18 April 2023. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoOutpatient Treatment of Confirmed COVID-19: A Living, Rapid Review for the American College of Physicians Isolde Sommer , Andreea Dobrescu , Dominic Ledinger , Isabel Moser , Kylie Thaler , Emma Persad , Martin Fangmeyer , Robert Emprechtinger , Irma Klerings , and Gerald Gartlehner Outpatient Treatment of Confirmed COVID-19: Living, Rapid Practice Points From the American College of Physicians (Version 1) Amir Qaseem , Jennifer Yost , Matthew C. Miller , Rebecca Andrews , Janet A. Jokela , Mary Ann Forciea , George M. Abraham , and Linda L. Humphrey , for the Scientific Medical Policy Committee of the American College of Physicians Metrics Cited byCorrection: Outpatient Treatment of Confirmed COVID-19 Current IssueMay 2023Volume 176, Issue 5KeywordsAntiviral therapyAntiviralsCOVID-19Drug therapyOmicron variantOutpatientsSystematic reviewsTreatment guidelines ePublished: 18 April 2023 Issue Published: May 2023 Copyright & PermissionsCopyright © 2023 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...